Bipolar disorder (BP) is one of the most debilitating and common illnesses worldwide. Individuals with BP frequently present to clinical services when depressed, but are often misdiagnosed with unipolar depression (UPD), leading to inadequate treatment and poor outcome. Increased accuracy in diagnosing BP, especially during depression, is therefore a key long term goal to help improve the mental health of individuals with BP. The attainment of this goal can be facilitated by identifying biomarkers reflecting pathophysiologic processes in BP - impaired emotion regulation, impaired attention and distractibility - that persist during depression and remission and are not common to UPD. As a first step toward this goal, this study employs a cross-sectional design and functional brain imaging to measure in individuals with the traditional BPI subtype functional abnormalities in brain systems underlying emotion processing (amygdala-centered) and working memory and attention (dorsolateral prefrontal cortex, DLPFC-centered) common to BPI depression and remission and BPI-specific. Second, we will employ a longitudinal design to measure relationships between changes in these brain system abnormalities and changes in depression severity over 6 months in BPI versus UPD. We will examine 1. 40 remitted BPI; 2. 40 depressed BPI; 3. 40 UPD; and 4. 40 healthy individuals. We will re- examine 20 individuals per group 6 months later. We will restrict medication combinations taken by patient participants to a small number to allow delineation of abnormal neural activity related to specific medications. We hypothesize that 1. BPI remitted and BPI depressed individuals will show abnormally increased amygdala and decreased DLPFC activity to positive and negative emotional stimuli, and decreased DLPFC activity during working memory; 2. UPD individuals will show increased amygdala activity to negative but not positive emotional stimuli; 3. decreased depression severity over time will be associated with decreased DLPFC activity during working memory in BPI, but with decreased amygdala activity to negative emotional stimuli in UPD. Relevance: BPI is a common, debilitating and potentially fatal disorder, often misdiagnosed as UPD. This study is directed at identifying biological markers of BPI that reflect pathophysiologic brain processes common to depression and remission and specific to BPI, as a first stage toward the long term goal of increasing diagnostic accuracy to help improve the mental heath of those with the disorder. [unreadable] [unreadable] [unreadable]